Synthesis of tris(β,β,γ-oximinoalkyl)amines from aliphatic nitro compounds and methyl vinyl ketone

Article abstract of DOI:10.1016/j.tetlet.2014.01.003

A general strategy for the assembly of previously unknown tris(β,β,γ-oximinoalkyl)amines from aliphatic nitro compounds and methyl vinyl ketone is described. The strategy involves N,N-bis(siloxy) enamines as key intermediates. The latter are accessible by double silylation of alkylnitro compounds. Nickel(II) and copper(II) complexes of tris(β,β,γ-oximinoalkyl)amines are prepared and structurally characterized.

Full text of DOI:10.1016/j.tetlet.2014.01.003

Accepted Manuscript
Synthesis of tris(β,β,γ-oximinoalkyl)amines from aliphatic nitro compounds
and methyl vinyl ketone
Elena A. Shalamova, Yeosan Lee, Garam Chung, Artem N. Semakin, Jinho Oh,
Alexey Yu. Sukhorukov, Dmitry E. Arkhipov, Sema L. Ioffe, Sergey E.
Semenov
PII:
S0040-4039(14)00008-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.003
TETL 44034
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 September 2013
26 November 2013
2 January 2014
Please cite this article as: Shalamova, E.A., Lee, Y., Chung, G., Semakin, A.N., Oh, J., Sukhorukov, A.Y., Arkhipov,
D.E., Ioffe, S.L., Semenov, S.E., Synthesis of tris(β,β,γ-oximinoalkyl)amines from aliphatic nitro compounds and
methyl vinyl ketone, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.01.003
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Synthesis of tris(β,β,γ-oximinoalkyl)amines
from aliphatic nitro compounds and methyl
vinyl ketone
Elena A. Shalamova, Yeosan Lee, Garam Chung, Artem N. Semakin, Jinho Oh, Alexey Yu.
Sukhorukov, Dmitry E. Arkhipov, Sema L. Ioffe, Sergey E. Semenov
R3
OH
O
R2
N
R1
R1
R4
[NH3]
N(OTMS)2
R4O NH2
N
R2
N
N
R3
O
OH
N(OTMS)2

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of tris(β,β,γ-oximinoalkyl)amines from aliphatic nitro compounds and
methyl vinyl ketone
Elena A. Shalamova,a Yeosan Lee,b Garam Chung,b Artem N. Semakin,a,c,* Jinho Oh,b Alexey Yu.
Sukhorukov,c,* Dmitry E. Arkhipov,d Sema L. Ioffe,a,c Sergey E. Semenovc
a Moscow Chemical Lyceum, Tamozhenniy proezd 4, 111033 Moscow, Russia;
b Korea Science Academy of KAIST, 105-47, Baegyanggwanmun-ro, Busanjin-gu, 614-822, Busan, Rep. of Korea;
c N.D. Zelinsky Institute of Organic Chemistry, Leninsky prospekt, 47, 119991 Moscow, Russia;
d A.N. Nesmeyanov Institute of Organic Chemistry, Vavilova St. 28, 119991, Moscow, Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A general strategy for the assembly of previously unknown tris(β,β,γ-oximinoalkyl)amines from
aliphatic nitro compounds and methyl vinyl ketone is described. The strategy involves N,N-
bis(siloxy)enamines as key intermediates. The latter are accessible by double silylation of
alkylnitro compounds. Nickel(II) and copper(II) complexes of tris(β,β,γ-oximinoalkyl)amines
are prepared and structurally characterized.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Oximes
Ligands
N,N-bis(siloxy)enamines
Michael addition
Amines
Tris(β,β,β-oximinoalkyl)amines (trisoximes) 1 are prospective
ligands for the design of biomimetic catalysts.1 Also, the
cyclization of the oxime groups in 1 results in the formation of
4,6,10-trihydroxy-1,4,6,10-tetraazaadamantanes 2 – derivatives
of a new class of heterocage compounds with a cage isomeric to
the well-known urotropine (1,3,5,7-tetraazaadamantane) (Scheme
1).2
The proposed scheme for the synthesis of trisoximes 4
includes the introduction of the two β-oximinoalkyl fragments
and one γ-oximinoalkyl fragment to ammonia (or a synthetic
equivalent of ammonia). In these approaches the introduction of
β-oximinoalkyl fragments by employing BENAs seems to be
logical, since they show high efficiency in the synthesis of
common trisoximes 1. For the introduction of the γ-oximinoalkyl
substituents we conceived tandem aza-Michael reactions then
oximation of the resulting aminoketone. It should be noted, that
the sequence of introduction of these fragments can be varied. In
accordance with this we considered several procedures for the
synthesis of various homotrisoximes 4.
Symmetrically substituted trisoximes 1, which were prepared
by the reaction of α-halooximes 3 with ammonia have been well
known for more than 100 years (Scheme 2).3 However, various
functionalized and unsymmetrically substituted trisoximes
became available only recently by using aliphatic nitro
compounds (ANCs) as starting materials (Scheme 2).4,5 The
strategy of ANC silylation to give the corresponding
N,N-bis(siloxy)enamines (BENAs) was exploited to achieve this
aim. BENAs, similarly to α-halooximes 3, serve as precursors for
generation of highly reactive nitroso-alkenes (NAs). However,
the use of BENAs allows the generation of NAs to be controlled
more effectively and provides good selectivity during the
process.6
The first route (Scheme 3) involves the synthesis of bis(β-
oximinoalkyl)amine 6 according to a literature protocol, followed
by its reaction with methyl vinyl ketone (MVK). Subsequent
oximation of the keto-group in aminoketone 7 by treatment with
hydroxylamine
in
methanol
furnished
the
desired
trimethylsubstituted homotrisoxime 4a. The use of O-methyl- or
O-benzylhydroxylamines in the oximation step provided the
corresponding homotrisoximes 8a and 8b in high yields.
In the present work we demonstrate that BENA can also serve
as convenient precursors for currently unknown trisoximes 4, or
homotrisoximes, which contain an additional methylene group in
one of the oximinoalkyl fragments compared to trisoximes 1
(Figure 1).
However, attempts to extend this approach to a range of other
α,β-unsaturated ketones [mesityl oxide CH3C(=O)CH=C(CH3)2
and
benzylideneacetone
CH3C(=O)CH=CHPh]
were
unsuccessful. No noticeable conversion of amine 6 was observed
in these experiments, probably, due to the higher steric hindrance
of the employed ketones compared to MVK. Furthermore, the
———
* Corresponding author
E-mail address: artyomsemakin@mail.ru (Artem N. Semakin).

2
Tetrahedron
reaction of bisoxime 6 with acrolein gave a complex mixture of
The possibility of intramolecular cyclization of the oximino-
unidentified compounds.
groups in oximes 4 was also investigated. In known trisoximes 1,
this process can be accomplished by treatment with protic acids
(AcOH, HCl, CF3CO2H).2 However, in the case of
homotrisoximes 4b, the formation of a cage structure was not
observed under these conditions (cf. Schemes 1 and 6).
Cyclotrimerization of oximes to 1,3,5-trihydroxy-1,3,5-triazines
is a thermodynamically unfavorable process.9 However, in the
case of tris(β,β,β-oximinoalkyl)amine 1a the lability of the
trihydroxytriazine ring is compensated by the enormous stability
of the adamantane cage in products 2 (see Scheme 1). We assume
that in homotetrazaadamantane cage 16a such a stabilization
effect is much smaller.
The second route to homotrisoximes 4 is based on an inverted
sequence of oximinoalkyl fragment introduction (a γ-
oximinoalkyl fragment followed by two β-oximinoalkyl
fragments, Scheme 4). The action of MVK with sodium azide
furnished azidoketone 9,7 which was then transformed into the
corresponding oxime by treatment with hydroxylamine. The
azido group in 9 was reduced into primary amine by catalytic
hydrogenation over palladium.5 The target homotrioximes 4a and
4b were obtained by addition of BENAa or BENAb to β-
aminooxime 11 in MeOH (Scheme 4).
Finally, it was demonstrated that the strategy could be
employed for the synthesis of unsymmetrically substituted
homotrisoximes (e.g., 4c). For this aim, mono(β-
oximinoalkyl)amine 12 was prepared according to the literature
procedure.5 Aza-Michael reaction of oxime 12 with MVK,
followed by oximation of the keto-group and subsequent
debenzylation of the product formed secondary amine 15. The
reaction of the amine 15 with 1.5 equiv. of BENAb gave the
desired homotrisoxime 4c (Scheme 5). Thus, the
unsymmetrically substituted trisoxime 4c was prepared in 32%
overall yield (in 5 steps).
In conclusion, several efficient approaches for the synthesis of
homotrisoximes 4 – analogues of previously known trisoximes 1
– are described employing aliphatic nitro compounds and methyl
vinyl ketone as starting materials.
Supplementary Material
Supplementary data (experimental procedures and spectral
data for all compounds) associated with this article can be found,
in the online version, at http://
The structures and purity of the products were confirmed by
1H and 13C NMR, high-resolution mass-spectrometry and
elemental analysis. The configuration of the C=N double bond in
the oximino-groups was determined as described in previous
work.4,5
Acknowledgments
This work was performed during an International
Collaborative Research Program between high-school students
from MCL and KSA of KAIST with financial support from MK-
3918.2013.3 and Program 8P of RAS Presidium grants.
The homotrisoximes 4 obtained can serve as chelating ligands.
Thus, reactions of trisoxime 4a with nickel(II) or copper(II)
chlorides gave the corresponding metal complexes. The
structures of these complexes were determined by X-ray
crystallography (Figures 2 and 3).8
References and notes
In both complexes, tris(β,β,γ-oximinoalkyl)amine 4a behaves
as a tetradentate ligand. A comparison of the structure of
complex [4a•NiCl2] with the structure of known similar
complex1b of tris(β,β,β-oximinoalkyl)amine 1a (R1 = R2 = R3 =
Me) demonstrates that the additional methylene group results in
closer to the ideal octahedral geometry of a nickel coordination
sphere. In particular, cis-angles N(1)Ni(1)N(4), N(2)Ni(1)N(4)
and N(3)Ni(1)N(4) in [4a•NiCl2] are 93.05(5)°, 79.79(5)° and
78.45(5)°, and the trans-angle Cl(1)Ni(1)N(4) is 168.80(4)°.
Corresponding cis-angles in [1a•NiCl2] are 80.54(5)°, 79.65(5)°
and 77.91(5)°, and the trans-angle ClNiN is 166.45(4).1b The
equatorial plane Ni(1)N(1)N(2)N(3)Cl(2) in [4a•NiCl2] is
significantly less distorted compared to the complex [1a•NiCl2]
(maximal deviations of atoms from the mean plane are 0.106Å
and 0.209Å, respectively).1b Evidently, this is due to the
formation of a more flexible six-membered chelate ring in
[4a•NiCl2] involving an additional methylene group. In complex
[4a•NiCl2] OH-groups of one β- and one γ-oximinoalkyl
fragments are involved in intramolecular hydrogen bonds with
the coordinated chlorine atom Cl(1) (the distances O(1)…Cl(1)
and O(2)…Cl(2) are 2.977Å and 3.116Å, respectively).
1. (a) Goldcamp, M. J.; Robinson, S. E.; Krause Bauer, J. A.;
Baldwin, M. J. Inorg. Chem., 2002, 41, 2307; (b) Goldcamp, M.
J.; Edison, S. E.; Squires, L. N.; Rosa, D. T.; Vowels, N. K.;
Coker, N. L.; Krause Bauer, J. A.; Baldwin, M. J. Inorg. Chem.,
2003, 42, 717; (c) Edison, S. E.; Hotz, R.P.; Baldwin, M. J. Chem.
Commun., 2004, 1212.
2. Semakin, A. N.; Sukhorukov, A. Yu.; Lesiv, A. V.; Ioffe, S. L.;
Lyssenko, K. A.; Nelyubina, Yu. V.; Tartakovsky, V. A. Org.
Lett., 2009, 11, 4072.
3. (a) Matthaiopoulos, G.; Chem. Ber. 1898, 31, 2396; (b) Korten,
H.; Scholl, R.; Chem. Ber. 1901, 34, 1904.
4. Semakin, A. N.; Sukhorukov, A. Yu.; Lesiv, A. V.; Khomutova,
Yu. A.; Ioffe, S. L. Synthesis, 2007, 2862.
5. Semakin, A. N.; Sukhorukov, A. Yu.; Ioffe, S. L.; Tartakovsky,
V. A. Synthesis, 2011, 1403.
6. Ioffe, S. L. “Nitrile oxides, nitrones, and nitronates in organic
synthesis”, 2nd ed.; Feuer, H., Ed.; John Wiley & Sons: Hoboken,
2008; Chapter 3.
7. Davies, A. J.; Donald, A. S. R.; Marks, R. E. J. Chem. Soc. C,
1967, 2109.
8. CCDC 958812 (for [4a•CuCl]Cl ) and 958813 (for [4a•NiCl2] )
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif
9. Jensen, K. A.; Holm, A. Danske Vid. Selsk. Mat. fys. Medd., 1978,
40, 1.

3
Scheme 1. Cyclization of tris(β-oximinoalkyl)amines into 4,6,10-trihydroxy-1,4,6,10-tetraazaadamantanes
Scheme 2. Synthesis of tris(β-oximinoalkyl)amines
Figure 1. Tris(β-oximinoalkyl)amines and their homologues

4
Tetrahedron
Scheme 3. Reagents and conditions: (i) 0.45 eq. BnNH2, CH2Cl2, then MeOH; (ii) 1 atm. H2, Pd/C (10%); (iii) 1.2 eq. MVK,
MeOH; (iv) 1.5 eq. NH2OH, MeOH; (v) 1.2 eq. R’ONH2•HCl, 1.2 eq. K2CO3, MeOH
Scheme 4. Reagents and conditions: (i) 2 eq. NaN3, AcOH/H2O; (ii) 1.5 eq. NH2OH, MeOH; (iii) 1 atm. H2, Pd/C (10%); (iv) 3
eq. BENAa or BENAb, MeOH
i: 12 eq.
Scheme 5. Reagents and conditions: (i) 12 eq. BnNH2, then MeOH; (ii) 1.5 eq. MVK, MeOH; (iii) 1.5 eq. NH2OH, MeOH; (iv)
1 atm. H2, Pd/C (10%); (v) 1.5 eq. BENAb, MeOH

5
Figure 2. ORTEP plot of the X-ray crystal structure of complex [4a•NiCl2] (thermal ellipsoids are drawn at the 50% probability
level). The H(C) hydrogens are omitted for clarity.
Figure 3. ORTEP plot of the X-ray crystal structure of complex [4a•CuCl]Cl (thermal ellipsoids are drawn at the 50%
probability level). The H(C) hydrogens and Cl2 are omitted for clarity.
Scheme 6. Attempted cyclization of 4a into homoadamantane 16a